Non-steroidal anti-inflammatory drugs such as those belonging to the category of cyclo-oxygenase-2 inhibitors including Nimesulide are highly hydrophobic compounds and readily precipitate even in the presence of minor amounts of water.
It is therefore very difficult to formulate non-steroidal anti-inflammatory drugs which are inhibitors of cycle-oxygenase-2 as an injectable composition for intramuscular or intravenous use.
In the past, efforts have been made to make an injectable composition of Nimesulide.
An injectable formulation of Nimesulide has been reported in PCT Patent No. WO 95/34533 which discloses utilizing a salt form of Nimesulide with L-lysine which is in turn further complexed with cyclodextrins which may be dissolved in water to give an injectable preparation. The maximum solubility achieved by this injectable composition was reported to be 2.4 mg/ml which is not sufficient for intramuscular administration as it would require very large volumes to administer therapeutic doses. Moreover making a salt form of Nimesulide and then combining with Cyclodextrins not only makes the process cumbersome but also increases the cost of the formulations.
Another reference (Daffonchio, L. et al. Inflammatory Research 45: 259-264; 1995) wherein Nimesulide is dissolved in saline for intravenous administration for experimental studies in animals also describes only very dilute solutions which cannot deliver therapeutic doses in humans.
The disadvantages of WO 95/34533 and problems associated therewith were overcome by the invention described in U.S. Pat. No. 5,688,829 (Corresponding Korean Application No. 96-48013, Australian Application No. 67993/96 and Japanese Patent Application No. 8-290585, all pending) by the inventors of the present invention.
This invention utilizing solubilization techniques was able to achieve sufficiently high concentrations of Nimesulide suitable to deliver therapeutic doses in conveniently small volumes using a base which was oily in nature without using water and without any salt form or complexing agents of Nimesulide.
The present invention comprises a composition wherein all the ingredients of the base are hydrophilic. The hydrophilic base serves the advantage of better miscibility with body fluids, faster drug disposition and better compatibility with the tissue environment.
It is an objective of the present invention to provide an injectable analgesic hydrophilic composition of non-steroidal anti-inflammatory drugs which are non-intensely colored and have better miscibility with body fluids. The hydrophilic compositions described herein can be administered both intravenously and intramuscularly.
It is another objective of the present invention to provide a novel process for the preparation of a parenteral hydrophilic injectable composition of NSAIDs.